PROJECT SUMMARY/ABSTRACT Mechanisms for memory formation and consolidation have been intensely studied for decades. Surprisingly, the process of forgetting, presumably of equal importance, has been virtually ignored. Fortunately, this focus is shifting and recent neuroscience-based interest in understanding how memories are forgotten has emerged. It is thought that forgetting enhances memory flexibility, by reducing the influence of obsolete information. In addition, forgetting may remove specific details of previous experiences, thereby promoting generalization. Thus, forgetting allows intelligent decision-making in an ever-changing and noisy environment. Research on forgetting is important not only because it will increase our understanding of how memories are processed by the brain but also because many psychiatric disorders may be associated with deficits in forgetting. This is a fledgling field in the study of learning and memory that will take great importance in the future years. Molecular, cellular and systems neuroscience studies using Drosophila have uncovered several major tenets that reveal the logic by which olfactory memories are formed, consolidated and retrieved. The first is that modulation of mushroom body (MB) Kenyon cell (KC) synaptic activity underlies associative learning. A second tenet is that the modulation of KC plasticity employs cAMP signaling. A third is that the mushroom body output neurons (MBOn) receive input from the KC and their activation influences approach or avoidance behavior. A fourth tenet is that dopamine neurons (DAn) are activated by aversive or rewarding stimuli to provide the US input during classical conditioning. Most recently, studies have started to shed some light on the antagonist process to memory acquisition and consolidation, i.e., memory forgetting. Recent molecular genetic studies have identified a role for the small G protein Rac1 in forgetting of olfactory memories. In addition, the dopamine receptor Damb, mediates the process of forgetting and this dopaminergic activity is modulated with the behavioral state of the animal. The current project seeks to build on our current understanding of memory loss by exploring a relatively new role for multidomain scaffolding protein, Scribble. The long-term goal is to define the molecular and functional nature of this scaffolding protein and its interacting proteins. Aim 1 will increase our basic understanding of how Scribble regulates forgetting by untangling the complexity of its gene and the multidomain protein as well as by revealing its subcellular localization. Aim 2 will dissect the molecular architecture of the forgetting signalosome. We will identify Scribble?s protein-protein interactions with the likelihood that we will find additional molecules involved in the regulation of forgetting. Aim 3 will explore the neural correlates of memory forgetting, by following the progression of the neuronal plasticity observed in MBOn and how is this plasticity affected by Scribble and other forgetting regulators like Rac. The significance of the current proposal resides in our poor current understanding of how memories are forgotten.